Alcoholic Liver Disease

Contents
• Introduction
• Pathogenesis
• Risk Factors
• Clinical Presentations
• Prognosis
• Treatment
 Introduction
• Chronic and excessive alcohol ingestion is
one of the major causes of liver disease.

• Three major lesions:

(1) Fatty liver,
(2) Alcoholic hepatitis, and
(3) Cirrhosis.
PATHOGENESIS OF ALCOHOLIC
LIVER DISEASE:
THE IMPORTANCE OF THE INNATE
BACKGROUND
 Genetic factors
• Genes influence the predisposition to
– alcohol dependence,
– sensitivity to alcohol and
– ALD cirrhosis development.
• Genes include those encoding for
– Alcohol-dehydrogenase (ADH),
– Aldehyde-dehydrogenase (ALDH) and
– C2-promoter allele of the gene coding for
cytochrome CYP2E1.
• Variants of ADH genotypes might facilitate
liver damage by
– either delaying acetaldehyde formation,
– allowing higher alcohol intakes, or
– diverting alcohol metabolism through non-
ADH pathways, such as the CYP2E1 and
– other non-oxidative pathways, which are
potentially more toxic to the liver.
• ALDH gene polymorphisms influence
alcohol sensitivity in
– some populations (e.g. Asian) and
– women, who develop ALD even consuming
low amounts of alcohol.
• Polymorphism of CYP2E1 gene (C2-
promoter allele) significantly differs among
races and heavy drinkers with ALD.

• Alcohol consumption induces CYP2E1 and

people with the C2-promoter allele exhibit a
far greater ability to metabolise alcohol.
• This might increase free radical generation
and lipid peroxidation, which promotes
fatty change in the liver.

• At present, the association between ALD

and the polymorphism of genes encoding
for ADH, ALDH and CYP2E1 is far from
being defined.
 Gender
• Women seem to develop ALD after the
ingestion of less than half the amount of
alcohol in men.
 Ethnic differences
• In the United States, cirrhosis rates are
higher in black men than in whites, while
Hispanics present the highest cirrhosis
mortality.
• Among active drinkers, Hispanics and
blacks are more likely to have a two fold
increase in serum aspartate
aminotransferase and GGT when compared
to whites.
PATHOGENESIS OF ALCOHOLIC
LIVER DISEASE: THE
MECHANISMS OF LIVER
DAMAGE
 Energy metabolism
• Rate of ATP synthesis is reduced.

• Chronic alcohol consumption depresses the

activity of all mitochondrial complexes,
except complex II, as several abnormalities
in mitochondrial respiratory chain.
• These include: decreased activity and heme
content of cytochrome oxidase, impaired
electron transport and proton translocation
through complex decreased cytochrome b
content in complex III and reduced function
in ATP synthase complex.

• As a result, the energy metabolism of liver

cells can be severely impaired and this
would lead to tissue damage.
• Hypoxia

• Chronic ethanol administration definitely

enhances the oxygen uptake rate by liver
cells because of the need of its
metabolization, which mainly occurs in the
centrilobular area of the liver lobule.
• Hemodynamic changes are mediated by an
imbalance between nitric oxide/endothelin-
1 interaction.

• Ethanol-induced vasoconstriction is
inhibited by endothelin-1 antiserum and
enhanced by nitric oxide synthase inhibitor
L-NMMA.
• At high ethanol blood levels, hypoxia might
ensue from the combination of reduced
perfusion and increased oxygen demand.

• When blood ethanol levels subsequently

decline, lobular perfusion is restored and
this can lead to reperfusion injury.
 Oxidative stress
• Oxidation of ethanol to water and carbon
dioxide is mediated by three major hepatic
enzyme systems:
– ADH in cytoplasm,
– Microsomal ethanol oxidizing system in
smooth ER of mitochondria (predominantly
CYP2E1) and
– Catalase in peroxisomal membrane.
• Alcohol leads to increased liver oxidative
stress via generation of highly reactive
oxygen species (ROS) and adducts.
ADH generates acetaldehyde,
which is subsequently
oxidized to acetate by ALDH.
Acetaldehyde can form
hybrid-adducts with reactive
residues (e.g.
malondialdehyde adduct)
acting on proteins or small
molecules (e.g. cysteines),
mediating lipid peroxidation
and nucleic acid oxidation
• Mitochondria represent a main site where
huge amount of ROS are generated,
leading, in turn, to cell damage and
necrosis.

• The NADH-induced inhibition of

mitochondrial b-oxidation leads to
accumulation of intracellular lipids, thus
promoting steatosis.
• Excessive alcohol consumption is also
associated with the enzymatic induction of
CYP2E1 pathway of alcohol metabolism.
The recruitment of this pathway may
indirectly contribute to ALD development
by excess production of superoxide radicals
via the interaction of CYP2E1 with
cytochrome reductase, which leads to
electron leaks in the respiratory chain and
ROS production.
• The species produced in this cascade can
interact with iron (Fenton reaction)
generating even more potent hydroxyl,
ferryl and perferryl radicals which
perpetuate liver damage.
 Immunologic mechanisms
• Alcohol intake increases the intestinal
permeability to a variety of substances that
include bacterial endotoxins, such as
lipopolysaccharide.

• Lipopolysaccharide ‘sensitises’ Kupffer

cells by binding with the CD14 receptor.
• This bond activates the nuclear factor
kappa B which, in turn, causes exaggerated
transcription of pro-inflammatory cytokines
such as TNF-a, IL-6 and (TGF-beta).
• TNF-alpha and IL-6 are mainly involved in
cholestasis and synthesis of acute-phase
proteins,

• TGF-beta may be critically involved in

fibrogenesis through the activation of
hepatic stellate cells.
• Last scenario should be characterized by
necro-inflammation, apoptosis and
fibrosis, which lead to the progression of
liver disease, finally leads to cirrhosis.
 PATHOGENESIS OF ALCOHOLIC LIVER
DISEASE: THE FAVOURING CONDITIONS
 Nutritional factors
Malnutrition
• Abusers substitute their daily nutritious
calories with the ‘empty’ calories provided
by ethanol.
• Other factors include
– Abnormal digestion,
– Increased skeletal and visceral protein
catabolism and
– Abnormalities in lipid metabolism.
• Malnutrition also increases the oxidative
stress by reducing the assumption and
promoting the depletion of endogenous
antioxidants (glutathione and vitamins A, E
and C).

• Patients with ALD are often deficient in

folate, thiamine and pyridoxine, which
enhance the likelihood of developing
anaemia, altered cognitive states and
night blindness.
Hepatotoxic co-morbid conditions
• Chronic alcoholics exhibit a significant
increase in hepatic iron concentration.

• ALD patients have an elevated hepatic iron

uptake in hepatocytes and Kupffer cells.
• Up to 70% of hepatitis C virus (HCV)
infected patients have a history of alcohol
abuse.

• 30% of patients with ALD are infected by

HCV.

• Alcohol intake appears to accelerate the

progression of chronic hepatitis C to
cirrhosis.
• Activation of pro-inflammatory cytokines
coupled with the direct dual hepatotoxic
effect of both HCV and alcohol may
accelerate the cyclic bouts of necrosis and
fibrosis leading to cirrhosis.
Potential pathophysiologic mechanisms for
fatty liver include the following:
• Decreased mitochondrial fatty acid beta-
oxidation
• Increased endogenous fatty acid synthesis or
enhanced delivery of fatty acids to the liver
• Deficient incorporation or export of
triglycerides as very low-density lipoprotein
(VLDL).
• Fatty liver is present in >90% of binge and
chronic drinkers

• The prognosis of severe ALD is dismal

• Mortality of patients with alcoholic

hepatitis concurrent with cirrhosis is nearly
60% at 4 years
 Pathology
• Fatty liver is the initial and most common
histologic response to hepatotoxic stimuli,
including excessive alcohol ingestion.

• Accumulation of fat within the perivenular

hepatocytes coincides with the location of
alcohol dehydrogenase, the major enzyme
responsible for alcohol metabolism.
• Continuing alcohol ingestion results in fat
accumulation throughout the entire hepatic
lobule.

• Appearance of
– steatohepatitis
– giant mitochondria,
– perivenular fibrosis, and
– macrovesicular fat may be associated with
progressive liver injury.
• Hallmark of alcoholic hepatitis is
hepatocyte injury characterized by
– ballooning degeneration,
– spotty necrosis,
– polymorphonuclear infiltrate, and
– fibrosis in the perivenular and perisinusoidal
space .
• Mallory bodies are often present

• Alcoholic hepatitis is thought to be a

precursor to the development of cirrhosis.
• Fatty liver, it is potentially reversible with
cessation of drinking.

• Cirrhosis is present in up to 50% of patients

with biopsy-proven alcoholic hepatitis and
its regression is uncertain, even with
abstention.
 Risk Factors
Risk Factor Comment
Quantity In men, 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years
causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic
liver disease.
Gender Women exhibit increased susceptibility to alcoholic liver disease at
amounts >20 g/d; two drinks per day probably safe.
Hepatitis C HCV infection concurrent with alcoholic liver disease is associated with
younger age for severity, more advanced histology, decreased survival.
Genetics Gene polymorphisms may include alcohol dehydrogenase, cytochrome
P4502E1, and those associated with alcoholism (twin studies).
Malnutrition Alcohol injury does not require malnutrition, but obesity and fatty liver
from the effect of carbohydrate on the transcriptional control of lipid
synthesis and transport may be factors. Patients should receive vigorous
attention to nutritional support.
 Clinical Features
• Right upper quadrant
discomfort,
• Tender hepatomegaly,
• Nausea,
• Jaundice
• Fever, spider nevi, jaundice,
and abdominal pain simulating
an acute abdomen represent the
extreme end of the spectrum
• Portal hypertension,
• Ascites, or
• Variceal bleeding
 Laboratory Features
• In fatty liver Abnormalities are nonspecific
and include modest elevations of the
– Aspartate aminotransferase (AST),
– Alanine aminotransferase (ALT), and
– Gamma glutamyl transpeptidase (GGTP),
– Hypertriglyceridemia,
– Hypercholesterolemia,
– Hyperbilirubinemia (occasionally )
• In alcoholic hepatitis
– AST and ALT are usually elevated two- to
seven fold.
• They are rarely >400 IU, and the AST/ALT ratio >1.
– Hyperbilirubinemia (common)
– Modest increases in the ALP
– Derangement in hepatocyte synthetic function
– Hypoalbuminemia and coagulopathy
 Laboratory Diagnosis of Alcoholic Fatty
Liver and Alcoholic Hepatitis
Test Comment
AST Increased two- to seven fold, <400 U/L, greater
than ALT
ALT Increased two- to seven fold, <400 U/L
AST/ALT Usually >1
GGTP Not specific to alcohol, easily inducible, elevated
in all forms of fatty liver
Bilirubin May be markedly increased in alcoholic hepatitis
despite modest elevation in alkaline phosphatase

PMN If >5500/L, predicts severe alcoholic hepatitis

when discriminant function > 32
 Prognosis
• Critically ill patients with alcoholic
hepatitis have short-term (30 day) mortality
rates >50%.
• Severe alcoholic hepatitis is heralded by
– Coagulopathy (prothrombin time > 5 s),
– Anemia,
– Serum albumin concentrations <25 g/L (2.5 mg/dL),
– Serum bilirubin levels > 137 micromole/L (8 mg/dL),
– Renal failure, and
– Ascites.
• A discriminant function calculated as 4.6 x
[prothrombin time - control (seconds)] +
serum bilirubin (mg/dL) can identify
patients with a poor prognosis (discriminant
function > 32).
• Presence of ascites, variceal hemorrhage,
deep encephalopathy, or hepatorenal
syndrome predicts a dismal prognosis.
 Treatment
• Complete abstinence from alcohol

• Nutritional and psychosocial states should

be evaluated.
Treatment
• Patient with a discriminant
function > 32, were given
prednisone, 40 mg/d, or
prednisolone, 32 mg/d, for 4
weeks followed by a steroid
taper.
• Nonspecific TNF inhibitor,
pentoxifylline, recently
demonstrated improved
survival in the therapy of
severe alcoholic hepatitis